Functions of thyroid hormone in retinal development

色觉依赖于视蛋白光色素在视网膜锥状光感受器中的不同表达，视蛋白光色素赋予对可见光光谱不同区域的敏感性。大多数哺乳动物是二色的，表达视蛋白，对中长（M，绿色）或短（S，蓝色）波长的光敏感。人类拥有这一系统，但由于基因复制产生了对长波（L，红色）光敏感的另一种视蛋白基因，因此具有三色功能。不同模式视蛋白的机制对颜色视觉至关重要。然而，潜在的信号和遗传控制在很大程度上仍然难以捉摸。我们对Thrb甲状腺激素受体基因的研究发现，在小鼠模型中，甲状腺激素受体TRb2在视锥细胞亚群中M和S视蛋白表达的多样化中发挥了意想不到的关键作用。TRb2的缺失导致M视蛋白的缺失，揭示了TRb2在视蛋白模式中的关键作用。这一意想不到的发现提出了关于内分泌和视觉系统之间联系的问题。以前，在对人类或哺乳动物模型物种甲状腺疾病的研究中，色觉缺陷的可能性在很大程度上被忽视了。该项目旨在研究TRb2和甲状腺激素如何调节视锥细胞的发育，并研究哪些基因可能在颜色视觉系统中与Thrb合作。进展:

Color vision depends upon the differential expression in retinal cone photoreceptors of opsin photopigments that confer sensitivity to different regions of the visible light spectrum. Most mammalian species are dichromatic and express opsins for sensitivity to medium-longer (M, green) or short (S, blue) wavelengths of light. Humans share this system but have trichromatic function because of a gene duplication that created another opsin gene for sensitivity to long wave (L, red) light. The mechanisms that differentially pattern opsins are critically important for color vision. However, the underlying signals and genetic controls have remained largely elusive. Our study of the Thrb thyroid hormone receptor gene identified an unexpectedly critical role for a thyroid hormone receptor, TRb2, in the diversification of M and S opsin expression in sub-populations of cones in a mouse model. Deletion of TRb2 results in a loss of M opsin, revealing a key role for TRb2 in opsin patterning. The unexpected nature of this finding raises questions regarding the link between the endocrine and visual systems. Previously, in the study of thyroid disorders in humans or in mammalian model species, the possibility of color visual deficiencies had been largely overlooked. The project aims to investigate how TRb2 and thyroid hormone regulate cone development and to investigate which genes may cooperate with Thrb in the color visual system. Progress: 1. Thyroid hormone administration was found to modify the timing and pattern of opsin expression in neonatal cone development in a mouse model, supporting the hypothesis that the hormonal ligand is important in modifying TRb2 activity in cone development. Additional studies are testing the consequences of a lack of thyroid hormone at sensitive, early stages of retinal development. These studies would indicate opsin abnormalties or other cone defects that may potentially arise in developmental thyroid disorders. 2. Candidate genes that may cooperate with the Thrb gene in the development of cone photoreceptors include those encoding deiodinase enzymes that could activate or inactivate thyroid hormone in the retinal target tissues at key stages in development. Ongoing studies have identified deiodinase expression in the neural retina at embryonic and neonatal stages. Studies in mouse genetic models suggest the functional importance of deiodination in cone development. The findings suggest the multi-genic nature of the controls that direct the development of cone photoreceptors and the function of the color visual system.